Deciphering how networks of interlinked transcription factors coordinate heart gene expression is essential for the diagnosis and treatment of congenital heart disorders. Our long-term goal is to gain a comprehensive understanding of chordate heart gene networks and how the conserved cardiac transcription factor, Ets, impacts early heart formation. The complexity of this process in vertebrate embryos has hindered progress. We have begun to exploit the simplicity of Ciona intestinalis, a close evolutionary relative of the vertebrates, to investigate a conserved role for Ets in early heart development. Our specific hypothesis is that Ets works in tandem with a lineage specific co-factor to establish heart progenitor identity. This hypothesis is based on three sets of observations. 1. Ets activity is both necessary and sufficient for heart progenitor gene expression. 2. Paired binding motifs for Ets and a presumptive co-factor are required for heart progenitor gene regulation. 3. Detection of paired Ets+co- factor motifs reveals new heart progenitor regulatory elements. The proposed specific aims focus on determining the precise transcriptional role of Ets in the heart progenitor gene network. Our efforts will initially focus on identification of the presumptive Ets co-factor. We will then begin to elucidate how Ets and this co-factor directly regulate a defined set of primary heart genes. We will also focus on developing cutting edge technology for comprehensive analysis of Ets/Co-Factor binding patterns during establishment of the heart lineage. These efforts will be tailored to promote intensive training of undergraduate researchers in the formulation and execution of independent research projects.

Public Health Relevance

Human heart defects are pervasive and the underlying genetic causes are often poorly understood. We are using sea squirt embryos, simple marine invertebrates with a surprisingly close relationship to humans, to study heart genetics. By studying the simple interconnections between heart genes in sea squirts, we aim to unravel the much denser and complex networks of genes that control human heart formation.